The thymus becomes significantly atrophied with age and less functional resulting in a lower production of nave T cells, a decline in the cell-mediated immune function and reduced resistance to infections. Aging has also been associated with increases in inflammation and inflammatory disease states. Several hormones including growth hormone (GH) and insulin growth factor-1 (IGF-1) have been shown to influence thymic and bone marrow development and activity in both the young and aged hosts. Our studies have revealed that a regulatory link exists between the "hunger" hormone ghrelin and the satiety hormone leptin in the regulation of immune responses. We have previously reported that the ghrelin and leptin are expressed by immune cells and regulate T-cell activation and inflammation. Our current efforts have demonstrated that both ghrelin and ghrelin receptor expression within the thymus diminishes with progressive aging. Infusion of ghrelin into old mice significantly improves the age-associated changes in thymic architecture and thymocyte counts and increases thymic T cell output and the peripheral TCR diversity of CD4+ and CD8+ T cells. Ghrelin and GHS-R deficient mice display enhanced age-associated thymic involution with reduced thymopoiesis and contraction of hematopoietic stem cell compartment. The accelerated thymic involution observed in GHS-R knockout mice was reflected in major perturbations in the TCR repertoire of peripheral T lymphocyte subsets. Similarly, leptin infusion into old mice demonstrated similar effects on thymic progenitors and thymic involution as was observed using ghrelin, GH and IGF-1. Ongoing studies with ghrelin, leptin and GH using transgenic and knockout mouse models have focused on the potential pathways and mechanisms by which these mediators influence bone marrow and thymic activity in the context of age, inflammation and stress. We believe that these hormone-induced changes occur via distinct signaling pathways and that each hormone may mediate their effects on distinct bone marrow and thymus subpopulations. These findings suggest a novel role for metabolic hormones and their receptors in bone marrow and thymic biology. Moreover, given our previous reports demonstrating ghrelin to be a potent anti-inflammatory agent in rodent and human immune responses, our recent efforts have also focused on defining the various cell signaling pathways by which these hormones mediate their effects on cell growth, activation and cytokine expression in both T cells and monocytes. Several unique pathways have been identified and we are currently working on completing these studies for publication. Overall, we believe that there is a functional immunoregulatory network involving orexigenic and anorexigenic hormones that control immune cell activation and differentiation, inflammation, hematopoiesis and cell survival. A greater understanding of this network may a means by which we can harness these hormonal pathways for therapeutic interventions such as reconstituting thymic function in the elderly and immunocompromised subjects and/or as anti-inflammatory agents in the treatment of autoimmune and inflammatory disease states.